1. Field of the Invention
The present invention relates to bis(5-aryl-2-pyridyl) derivatives or salts thereof, and also to medicinal compositions which comprise the bis(5-aryl-2-pyridyl) derivatives or salts-thereof as active ingredients and are useful for the prevention or treatment of allergic immune diseases.
2. Discussion of the Background
IgE, a class of immunoglobulin (Ig), is an allergen-specific molecule produced by IgE producing cells differentiated from B cells, when triggered by contact of immunocytes with an allergen in the body.
IgE is produced in an organ targeted by allergy, and binds to a receptor on-surfaces of mast cells which are the principal effector cells in an allergic reaction or basophils (sensitized state). From the mast cells, which are stimulated as a result of intrusion of the allergen into the body after sensitization and the accompanying reaction with the specific IgE, allergic chemical mediators such as histamine, leucotrienes, prostaglandins and PAF, and tissue destructive enzymes such as tryptase are released thereby provoking the immediate responses of an allergic reaction such as increased vasopermeability, smooth muscle constriction or vasodilation. From the stimulated mast cells, cytokines, such as IL-4, which directly activate other immune system cells are also secreted. As a result, eosinophils, basophils or the like infiltrate tissues, and allergic chemical mediators or tissue destructive proteins such as MBP, which are secreted by these inflammatory cells, induces late responses of an allergic reaction to protract and worsen an allergic symptom.
As can be appreciated from the foregoing remarks, an abnormality in IgE production is highly relevant to various allergic immune diseases such as asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis and allergic ophthalmopathy. It is known that inhibition of IgE production makes it possible to prevent and/or treat these diseases (Emerging Therapeutic Targets In Asthma And Allergy: Modulation Of IgE, Emerging Therapeutic Targets, 3, 229–240 (1990); Anti-IgE As Novel Therapy For The Treatment Of Asthma, Curr. Opin. Plum. Med., 5, 76–80 (1999); Treatment Of Allergic, Asthma With Monoclonal Anti-IgE Antibody, N. Eng. J. Med., 341, 1966–1973 (1999); Anti-IgE Antibody Therapy For Asthma, N. Eng. J. Med., 341, 2006–2008 (1999)).
From the foregoing, IgE is believed to be a substance which takes part in the manifestation of an allergic disease at the onset of the disease. With the objective of developing antiallergic agents, some small molecules with IgE antibody production inhibiting activity have been found and reported to date (WO 98/04058, WO 98/07702, WO 98/16497, JP 10-324631A, WO 99/19291, WO 99/35140, WO 99/38829, WO 99/42446, JP 11-269192A, WO 00/05198, “Yakuri to Chiryo (Basic Pharmacology & Therapeutic)” 22(3), 1369 (1994), JP 1-106818A, JP 7-17506B, JP 8-92216A, JP 8-109177A, WO 96/11682, JP 59-167564A). These compounds, however, involve problems such as low solubility in water, and therefore they are not entirely satisfactory agents in the therapeutic treatment of allergic disease.